Reflecting our clinical interest in epilepsy and other neurologic disorders of infants and children, our research this past 16 years has concerned brain ( and liver) metabolism in newborn and developing mice - the in vivo effects on the developing nervous system of ischemia and anoxia, undernutrition, vitamin deficiency, hormones, drugs, and poisons, of abnormal levels of metabolites that accumulate in the inborn errors of metabolism and other metabolic diseases and of common electrolyte distrubances. Our objective is a better understanding of the biochemical basis of clinical disease and poisoning in infants and children and the biochemical rationale for specific or other therapy. Reports of deaths in association with treatment with sodium valproate, a new anticonvulsant drug, are increasing. In preliminary studies we have found that valproate caused a critical reduction in plasma Beta-hydroxybutyrate levels and liver glycogen content in infant mice; plasma fatty acid and glycerol levels were normal. Reduced brain weight and electrolyte and metabolite changes suggested delayed cerebral matauration. The objective of the proposed research is to determine the mechanism of these findings. Greatly decreased ketogenesis during fasting in a 3-yr-old child receiving valproate suggests that the valproate-treated infant mouse will prove to be a satisfactory model of fatal valproate-associated hepatic dysfunction in infants and children. The capacity for ketone body production will be evaluated by measurements of triglycerides, faty acids and the glucagon/insulin ration in plasma and the NADH/NAD+ acetyl-CoA/CoA and acetyl-CoA/acetoacetyl-CoA concentration ratios in liver. We will study the effect of valproate on activities of hepatic enzymes of fatty acid metabolism ketogenesis, glycogen metabolism and gluconeogenesis. In brain we will determine the effect of hypoketonemia on growth (DNA and RNA content), on the activities of enzymes of ketone body utilization and on myelination. Specific microenzymatic techniques of metabolite assay and fluorometric, spectrophotometric and radiosotopic measurements of enzyme activities will be used.